Wolfram Hoetzenecker , Tarun Mehra , Ieva Saulite , Martin Glatz , Peter Schmid-Grendelmeier , Emmanuella Guenova , Antonio Cozzio , Lars E. French1
Dr. Arif Effendi Sp. KK
By : Dea Nabila Ratu Alicia
Abstrak
Toxic epidermal necrolysis (TEN) is a
rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. Introduction
The exposure to drugs has increased with
demographic shifts associated with a higher morbidity of the population. Along with this phenomenon, a rise in the incidence of adverse drug reactions (ADRs) has been observed. Toxic epidermal necrolysis (TEN) is a rare, acute, and life-threatening mucocutaneous disease that is usually drug related. Recent evidence situates TEN as the most severe form amongst a spectrum of severe epidermolytic adverse cutaneous drug reactions, which further include Stevens-Johnson syndrome (SJS) and the SJS- TEN overlap disease. TEN is a consequence of extensive keratinocyte cell death that results in the separation of significant areas of skin at the dermal-epidermal junction with the production of bullae followed by skin sloughing. This extensive cell death also leads to mucous membrane detachment and contributes to the characteristic symptoms of TEN, which include high fever, mucositis, and moderate to severe skin pain, anxiety, and asthenia. Clinical features The main symptoms of TEN are usually preceded by non-specific symptoms such as fever, stinging eyes, and discomfort upon swallowing by several hours up to several days. Characteristically, cutaneous lesions first appear in the presternal region as well as the face, palms, and soles of the feet. Mucosal involvement occurs in more than 90% of patients, predominantly affecting the mouth, genitalia, and/or ocular region. In some cases, the respiratory system and gastrointestinal tract are also affected. The morphology of lesions is characterized by erythema and erosions. Ocular involvement is frequent. Figure 1. Toxic epidermal necrolysis (TEN) after carbamazepine administration. (A) Skin detachment with facial erosions, including involvement of the lips and conjunctiva. (B) TEN with an extensive cutaneous involvement marked by detached and detachable apoptoticskin erosions on the trunk Pathogenesis So far, the precise molecular and cellular pathogenic mechanisms leading to the development of SJS/TEN can be only partially explained. It is thought to be initiated by an immune response to an antigenic drug-host tissue complex. Figure 2. Conceptual models concerning T cell stimulation by drugs in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). (A) Drugs inducing an adverse skin reaction are not antigenic by themselves. Instead, their immunogenicity may result from binding to carrier proteins, which allows the formation of neoantigens that are recognized by T cells upon presentation by antigen-presenting cells (APCs). (B) The p-i concept is based on the pharmacological interactions of drugs with immune receptors. Consistent with this concept, chemically inert drugs, which are unable to bind covalently to proteins, may activate specific T cells by binding directly to T cell receptors and/or major histocompatibility complex molecules. (C) The association of peptides with HLA molecules is highly specific. According to the “altered peptide model”, specific HLA molecules form a complex with certain drugs, thereby modifying the pool of self-peptides presented to T cells. This may result in increased autoimmunity. Concepts for immunological responses of SJS/TEN modified from Abe et al. Treatment The suspect drug should be discontinued immediately and supportive therapy should be ensured in the burn or intensive care unit. However, valid data on effective therapeutic options are poor, and prospective controlled clinical trials, which can clearly show the benefit of certain treatment options, are lacking. Some case reports and case series report a benefit of cyclosporine, cyclophosphamide, N-acetylcysteine, TNF-α antagonists (e.g. etanercept and infliximab), systemic corticosteroids (favoring pulsed corticosteroid treatment), thalidomide, plasmapheresis, and intravenous immunoglobulin (IVIG). Method performed skin patch testing to identify the causative agent in 17 patients who had suffered from SJS and/or TEN. Positive patch test reactions were observed in only 24% of those patients. The study was conducted at the Dermatology department of the University Hospital of Zürich, Zürich, Switzerland Discussion Conclusions. Since the time TEN was first described by Dr. Lyell, it has remained a deadly disease with a mortality of around 30%. There is an unmet need to study the pathophysiology of TEN in more detail, which is complicated by the rarity of this disease and the lack of appropriate mouse models. Additionally, effective therapeutic options validated by prospective, randomized, controlled trials remain to be discovered. The most important therapeutic measure so far remains the rapid identification and withdrawal of the causative drug in addition to supportive care. However, this can be a complicated task inpatients with polymedication. The allergologic work-up is further. THANK YOU...